Abstract 5129: Neutrophil extracellular traps induced by surgical stress regulate cancer metabolism leading to tumor growth
Authors: Tony Haykal, Ruiqi Yang, Celine Tohme, Ronghua Wang, David Geller, Christof Kaltenmeier, Hamza Yazdani, Samer Tohme
Journal: Cancer Research (2023)

Abstract Introduction: Surgery is a crucial intervention to cure malignancies. However, evidence shows that the surgical insult and its accompanying immune response can enhance tumor growth and metastasis. Neutrophil Extracellular Traps (NETs) released systemically during surgical stress were previously shown to contribute to this process. In fact, to generate increased energy demands required for growth and metastasis, cancer cells in a stressful microenvironment need an adaptive mechanism where metabolic reprogramming to fatty acid (FA) oxidation has been emerging as an important process. Here, we aim to explore the direct effects of surgical NETs in regulating cancer cell metabolism leading to tumor growth and metastasis. Methods: For the indolent tumor model, C57BL/6 mice were injected with a small number of LLC-1 (Lewis Lung Cancer-1) cells subcutaneously (SQ) and a group was subjected to laparotomy for 30 mins, with or without intraperitoneal DNAse (NET inhibitor) injection perioperatively. Tumor growth was then followed for 4 weeks. For the tumor metastasis model, LLC-1 cells were injected SQ and allowed to grow for 3 weeks before resection with or without perioperative DNAse. Tumor metastasis to the lungs was assessed after 3 weeks. In vitro experiments on LLC-1 and MC-38 (murine colon adenocarcinoma) cancer cells were performed using NETs released from neutrophils freshly isolated from mice bone marrow and stimulated with Phorbol myristate acetate (PMA). Results: For the indolent tumor model, injection of cancer cells did not lead to any significant tumor growth after 4 weeks unless mice underwent surgical stress via laparotomy. Treatment with DNAse significantly reversed their growth. For the tumor metastasis model, tumor resection alone led to significant lung metastasis, but DNAse treatment during resection or resection in PAD-4 KO mice (unable to form NETs) led to significantly less metastatic burden. Furthermore, in vitro treatment of cancer cells with NETs lead to significant cell proliferation, relatively more under hypoxic and serum conditions. This was paralleled with a significant increase in fluorescently labeled FA uptake into cancer cells as detected by flow cytometry, as well as a significant upregulation of gene expression of FA transport proteins and oxidation enzymes. Conclusion: Surgical stress can promote tumor growth and metastasis through cancer cell metabolic reprogramming induced by systemically released NETs. We hope that elucidating the molecular mechanism behind this process can help in finding therapeutics to prevent the protumorigenic effects of surgical stress. Citation Format: Tony Haykal, Ruiqi Yang, Celine Tohme, Ronghua Wang, David Geller, Christof Kaltenmeier, Hamza Yazdani, Samer Tohme. Neutrophil extracellular traps induced by surgical stress regulate cancer metabolism leading to tumor growth. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5129.